JP6523328B2 - Tannate sitagliptin complex - Google Patents
Tannate sitagliptin complex Download PDFInfo
- Publication number
- JP6523328B2 JP6523328B2 JP2016562508A JP2016562508A JP6523328B2 JP 6523328 B2 JP6523328 B2 JP 6523328B2 JP 2016562508 A JP2016562508 A JP 2016562508A JP 2016562508 A JP2016562508 A JP 2016562508A JP 6523328 B2 JP6523328 B2 JP 6523328B2
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- JP
- Japan
- Prior art keywords
- sitagliptin
- complex
- oral
- tannate
- oral administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims description 95
- 229960004034 sitagliptin Drugs 0.000 title claims description 93
- 229920002253 Tannate Polymers 0.000 title claims description 37
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 29
- 239000001263 FEMA 3042 Substances 0.000 claims description 20
- 229920002258 tannic acid Polymers 0.000 claims description 20
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- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 claims description 19
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Description
本出願は、シタグリプチン(4−オキソ−4−[3−(トリフルロロメチル(trifluroromethyl))−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミン)とタンニン酸との複合体(「タンニン酸シタグリプチン複合体」)に関し、これはジペプチジルペプチダーゼ−IV(「DPP−IV」)の強力な阻害剤である。この新規のタンニン酸複合体は、DPP−IVの阻害剤が適応される疾患および状態の処置、管理または予防に有用である。本発明はさらに、有効量のタンニン酸シタグリプチン複合体を含む経口剤形、有効量のタンニン酸シタグリプチン複合体を含む医薬中間体、有効量のタンニン酸シタグリプチン複合体をその必要がある患者に投与することによりDPP−IV阻害剤が適応される疾患または状態を処置、管理または予防する方法、およびタンニン酸シタグリプチン複合体を調製するプロセスに関する。 The present application relates to sitagliptin (4-oxo-4- [3- (trifluroromethyl))-5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazine-7 (8H) A complex of "-yl" -1- (2,4,5-trifluorophenyl) butan-2-amine "and tannic acid (" tantagnic acid sitagliptin complex "), which is a dipeptidyl peptidase-IV (" DPP-IV ") is a potent inhibitor. This novel tannic acid complex is useful for the treatment, management or prevention of diseases and conditions for which DPP-IV inhibitors are indicated. The present invention further provides an oral dosage form comprising an effective amount of sitagliptin tannate complex, a pharmaceutical intermediate comprising an effective amount of sitagliptin complex tannate, an effective amount of sitagliptin complex tannate to a patient in need thereof. The present invention relates to a method for treating, managing or preventing a disease or condition for which a DPP-IV inhibitor is indicated thereby, and a process for preparing tantagate sitagliptin complex.
DPP−IVはグルコース依存性インスリン分泌刺激ペプチド(GIP)およびグルカゴン様ペプチド1(GLP−1)の両方を不活性化する酵素であり、その阻害は非インスリン依存性糖尿病(NIDDM)としても知られる2型糖尿病の処置および予防のための新規アプローチを表す。2型糖尿病の処置のためのDPP−IV阻害剤の治療的可能性は、C.F.Deacon and J.J.Holst,”Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes:a historical perspective,”Biochem.Biophys.Res.Commun.,294:1−4(2000);K.Augustyns,et al.,”Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of type 2 diabetes,”Expert.Opin.Ther.Patents,13:499−510(2003);およびD.J.Drucker,”Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2 diabetes,”Expert Opin.Investig.Drugs,12:87−100(2003)で概説されている。 DPP-IV is an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), the inhibition of which is also known as non-insulin dependent diabetes (NIDDM) 10 depicts a novel approach for the treatment and prevention of type 2 diabetes. The therapeutic potential of DPP-IV inhibitors for the treatment of type 2 diabetes is as follows: F. Deacon and J. J. Holst, “Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective,” Biochem. Biophys. Res. Commun. , 294: 1-4 (2000); Augustyns, et al. , “Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of type 2 diabetes,” Expert. Opin. Ther. Patents , 13: 499-510 (2003); J. Drucker, “Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2 diabetes,” Expert Opin. Investig. Drugs , 12: 87-100 (2003).
Merck Sharp & Dohme Corp.に譲渡されたWO2003/004498は、ベータ−アミノテトラヒドロトリアゾロ[4,3−a]ピラジン類を記載しており、これはDPP−IVの強力な阻害剤であって、それ故に2型糖尿病の処置のために有用である。WO03/004498中で具体的に開示されているのは、4−オキソ−4−[3−(トリフルオロメチル)−5,6−ジヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン−7(8H)−イル]−1−(2,4,5−トリフルオロフェニル)ブタン−2−アミンである。この化合物の薬学的に許容される塩はWO03/004498の範囲内に包括的に包含されるものの、タンニン酸シタグリプチン複合体の具体的開示はない。 Merck Sharp & Dohme Corp. WO 2003/004498 assigned to: describes beta-aminotetrahydrotriazolo [4,3-a] pyrazines, which are potent inhibitors of DPP-IV and are therefore of type 2 diabetes Useful for treatment. Specifically disclosed in WO 03/004498 is 4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a]. Pyrazine-7 (8H) -yl] -1- (2,4,5-trifluorophenyl) butan-2-amine. Although pharmaceutically acceptable salts of this compound are generally included within the scope of WO 03/004498, there is no specific disclosure of tantag acid sitagliptin complex.
またMerck Sharp & Dohme Corp.に譲渡されたWO2005/003135は、シタグリプチンのリン酸二水素塩を開示している。この刊行物は、そのホスホン酸二水素塩がDPP−IVの強力な阻害剤であり、それ故に2型糖尿病とも呼ばれる非インスリン依存性糖尿病、肥満および高血圧の処置および予防のために有用であることを指し示している。WO2005/003135はまた、そのリン酸二水素塩の一水和物結晶、同様にその調製プロセス、この新規の塩形態を含有する医薬組成物、ならびに2型糖尿病、肥満および高血圧の処置のための使用方法を記載している。WO2005/003135は、タンニン酸シタグリプチン複合体を記載していない。全てMerck Sharp & Dohme Corp.に譲渡されたWO2005/072530、WO2006/033848およびWO2007/035198は、シタグリプチンの塩を記載している。 Also, Merck Sharp & Dohme Corp. WO 2005/003135, assigned to the United States, discloses the dihydrogen phosphate salt of sitagliptin. This publication states that the phosphonic acid dihydrogen salt is a potent inhibitor of DPP-IV and is therefore useful for the treatment and prevention of non-insulin dependent diabetes, also called type 2 diabetes, obesity and hypertension. Is pointing to WO 2005/003135 also describes monohydrate crystals of its dihydrogen phosphate, as well as its preparation process, pharmaceutical compositions containing this novel salt form, and for the treatment of type 2 diabetes, obesity and hypertension. Describes how to use. WO 2005/003135 does not describe tannin sitagliptin complexes. All Merck Sharp & Dohme Corp. WO 2005/072530, WO 2006/033848 and WO 2007/035198 assigned to describe the salts of sitagliptin.
タンニン酸は、タンニン、ガロタンニン、グリセリン剤(glycerite)またはガロタンニンとしても知られ、おおよその組成がC76H52O46であり分子量が約1701グラム/molであるやや黄色から淡褐色の非晶質粉末である。タンニン酸は典型的に没食子(Turkish nutgall)または五倍子(Chinese nutgall)から生産されるが、多くの植物の樹皮および果実に由来するものであることができる。タンニン酸は水、グリセリンまたはアルコール中に非常によく溶ける。タンニン酸は、天然物からの抽出により、または合成化学的合成を介して得られ得る。 Tannic acid, also known as tannins, gallotannins, glycerite or gallotannins, is a slightly yellow to light brown amorphous with approximate composition C 76 H 52 O 46 and a molecular weight of about 1701 grams / mole. It is a powder. Tannic acid is typically produced from Turkish nutgall or Chinese nutgall, but can be derived from the bark and fruits of many plants. Tannic acid dissolves very well in water, glycerin or alcohol. Tannic acid can be obtained by extraction from natural products or via synthetic chemical synthesis.
薬学的活性化合物を含むタンニン酸複合体は、当該技術分野で公知である。例としてUS5,663,415;US6,881,741B2;US6,939,856B2;US6,670,370B1;およびUS7,547,806B2を参照されたい。タンニン酸塩は、他の塩または遊離塩基の形態と比べて、より良好な感覚受容性、例えば味などを持つことが見出されている。例としてUS2005/0202050A1またはUS2003/0083354A1を参照されたい。また、Vummaneni et al.(International Journal of Research in Pharmaceutical and Biomedical Sciences 3(2),510−524(2012))は、タンニン酸はリン酸クロロキンに対する矯味剤として作用することを報告している。そのうえ、タンニン酸塩は比較的高分子であることから、長時間にわたって薬学的活性化合物の吸収を提供するものであり、したがって徐放調合剤において用いることができる。例としてUS7,547,806B2;US2005/0202050A1またはUS2003/0083354A1を参照されたい。 Tannic acid complexes containing pharmaceutically active compounds are known in the art. See, for example, US 5,663,415; US 6,881,741 B2; US 6,939, 856 B2; US 6,670,370 B1; and US 7,547,806 B2. Tannic acid salts have been found to have better organoleptic properties, such as taste, as compared to other salt or free base forms. See, for example, US 2005/0202050 A1 or US 2003/0083354 A1. Also, Vummaneni et al. ( International Journal of Research in Pharmaceutical and Biomedical Sciences 3 (2), 510-524 (2012)) report that tannic acid acts as a flavoring agent for chloroquine phosphate. Moreover, because tannate is a relatively high molecular weight, it provides absorption of the pharmaceutically active compound over time and can therefore be used in sustained release formulations. See for example US 7,547,806 B2; US 2005/0202050 A1 or US 2003/0083354 A1.
リン酸一水塩としてのシタグリプチンは、2型糖尿病を有する成人の血糖管理を改善するためのJANUVIA(登録商標)中の活性成分であり、JANUMET(登録商標)およびJANUMET XR(登録商標)中の活性薬剤のうちの1つであって、これら全てはMerck & Co.,Inc.の子会社であるMerck Sharp & Dohme Corp.により販売されている。シタグリプチンリン酸一水和物の意図せぬ効果は、強烈な長引く苦味を持つことである。この苦味を克服するため、シタグリプチンリン酸一水和物を含有する薬剤製品はフィルムコーティング錠として製剤化される。JANUMET(登録商標)を摂取する患者のうち推定で20%はこの錠剤を飲み込むのに困難を経験しているように、フィルムコーティング錠としてのシタグリプチンリン酸一水和物の販売は、常に理想的というわけではない。 Sitagliptin as a phosphate monohydrate is the active ingredient in JANUVIA® for improving glycemic control in adults with type 2 diabetes and in JANUMET® and JANUMET XR® One of the active agents, all of which are described in Merck & Co. , Inc. Merck Sharp & Dohme Corp., a subsidiary of Sold by. The unintended effect of sitagliptin phosphate monohydrate is to have a strong, prolonged bitter taste. To overcome this bitter taste, drug products containing sitagliptin phosphate monohydrate are formulated as film coated tablets. Sales of sitagliptin phosphate monohydrate as film-coated tablets are always ideal, as an estimated 20% of patients taking JANUMET® experience difficulties in swallowing this tablet Not that.
したがって、大きな錠剤を飲み込むことができない患者集団(例として高齢者または子供)のための心地よい味を有する代替的な口腔内剤形を開発する要求がある。そのうえ、これらの代替的口腔内剤形はいずれも、製品を費用対効果のあるものにするために製造が比較的容易でなければならない。この目的および他の目的は、以下の記載から明らかになるであろう。 Thus, there is a need to develop alternative oral dosage forms having a pleasant taste for a patient population (e.g. the elderly or a child as an example) who can not swallow large tablets. Moreover, any of these alternative oral dosage forms should be relatively easy to manufacture in order to make the product cost effective. This and other objects will become apparent from the following description.
その多く実施形態において、本発明は、シタグリプチンのタンニン酸複合体、有効量のタンニン酸シタグリプチン複合体を含む経口剤形、有効量のタンニン酸シタグリプチン複合体を含む医薬中間体、および有効量のタンニン酸シタグリプチン複合体をその必要がある患者に投与することによりDPP−IV阻害剤が適応される疾患または状態を処置、管理または予防する方法を対象とする。本発明はさらに、タンニン酸シタグリプチン複合体を調製するプロセスに関する。 In its many embodiments, the present invention provides a tannic acid complex of sitagliptin, an oral dosage form comprising an effective amount of sitagliptin complex tannate, a pharmaceutical intermediate comprising an effective amount sitagliptin complex tannate, and an effective amount of tannin Methods of treating, managing or preventing a disease or condition for which a DPP-IV inhibitor is indicated by administering acid sitagliptin complex to a patient in need thereof. The invention further relates to a process of preparing tantagate sitagliptin complex.
出願人は、タンニン酸シタグリプチン複合体が例えば口腔内などで見出される中性pHにおいてごくわずかな放出速度を呈し、例えば胃内などで見出される酸性pHにおいて即時放出を呈する放出特性またはプロファイルを有することを発見した。タンニン酸シタグリプチン複合体は口内であたりさわりのない味を持つため、この放出特性は、シタグリプチンを、飲み込みやすくフィルム層を必要としない経口剤形、例として例えばチュアブル錠、ソフトチュー(soft chew)、薬用ガムまたは崩壊錠(disintegrating table)などの剤形へと製剤化することを可能にする。そのうえ、あたりさわりのない味を持つ経口剤形は、薬摂取における患者コンプライアンスを改善することが期待される。 Applicants have that the tannin acid sitagliptin complex has a release profile or profile that exhibits a negligible release rate at neutral pH found eg in the oral cavity and eg immediate release at acidic pH found eg in the stomach etc. Found. This release profile makes sitagliptin easy to swallow, does not require a film layer, and so does an oral dosage form such as eg chewable tablets, soft chew, as the sitagliptin tannate complex has an open mouth taste in the mouth It can be formulated into a dosage form such as a pharmaceutical gum or disintegrating table. Moreover, oral dosage forms with a bland taste are expected to improve patient compliance in drug intake.
さらに、従来技術がタンニン酸複合体について一般的に教示していることを考慮すると、この放出特性は予期せぬものである。従来技術は、タンニン酸複合体は医薬品有効成分(API)を含む医薬製剤に長期放出特性を付与することを開示している(例としてUS6,670,370およびUS6,939,856を参照されたい)。持続放出特性を呈することは、持続放出医薬製剤中のAPIが例えば胃内などで見出される酸性pHにおいて安定であり(すなわち、ごくわずかな解離を呈し)、例えば腸内などで見出される中性pHにおいて予め決められたように経時的に解離することを意味する。しかしながら、本発明のタンニン酸シタグリプチン複合体の放出特性においては、意外なことに、酸性pHで即時放出が起こるという点で逆のことが起こる。 Furthermore, the release profile is unexpected given that the prior art generally teaches tannic acid complexes. The prior art discloses that tannic acid conjugates impart long-term release characteristics to pharmaceutical formulations containing active pharmaceutical ingredients (APIs) (see, for example, US 6,670,370 and US 6,939,856 ). Sustained-release characteristics indicate that the API in the sustained-release pharmaceutical preparation is stable at acidic pH found, for example, in the stomach (i.e. exhibits a slight dissociation), such as neutral pH found in the intestine, etc. It means to dissociate over time as previously determined. However, in the release profile of the tantagate sitagliptin complex of the present invention, surprisingly, the reverse occurs in that an immediate release occurs at acidic pH.
ある実施形態において、本発明は、タンニン酸シタグリプチン複合体を提供する。 In one embodiment, the present invention provides sitagliptin tannate complex.
本発明の別の実施形態は、シタグリプチン含量が約25重量%から約75重量%、または約29重量%から33重量%であるタンニン酸シタグリプチン複合体である。 Another embodiment of the present invention is sitagliptin tannate complex having a sitagliptin content of about 25 wt% to about 75 wt%, or about 29 wt% to 33 wt%.
本発明の別の実施形態は、タンニン酸に対するシタグリプチンの重量比が約3:1から約1:4;例えば重量比が1:2であるタンニン酸シタグリプチン複合体である。 Another embodiment of the present invention is sitagliptin tannate complex wherein the weight ratio of sitagliptin to tannic acid is about 3: 1 to about 1: 4; eg, 1: 2 weight ratio.
本発明の別の実施形態は、治療的有効量の請求項1に記載のタンニン酸シタグリプチン複合体および不活性担体を含む医薬組成物である。 Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of sitagliptin tannate complex according to claim 1 and an inert carrier.
本発明の別の実施形態は、治療的有効量の請求項1に記載のタンニン酸シタグリプチン複合体、治療的有効量の少なくとも1の付加的な薬学的活性成分(例としてビグアナイド、例えばメトホルミンまたは薬学的に許容されるその塩など)および不活性担体を含む医薬組成物である。 Another embodiment of the present invention is a therapeutically effective amount of sitagliptin complex tannate according to claim 1, a therapeutically effective amount of at least one additional pharmaceutically active ingredient (eg a biguanide such as metformin or a pharmaceutical) And the like) and an inert carrier.
本発明の別の実施形態は、薬学的有効量のタンニン酸シタグリプチン複合体、薬学的に許容されるポリマー(例としてポリエチレングリコール(PEG)、例えばPEG3350、PEG6000またはPEG8000など)を含み、および1または複数の薬学的に許容されるポリオール(例としてマンニトールまたはマルチトール)、高強度甘味料(例としてスクラロース)または香味料(例としてミント、サクランボまたはバナナ風味)を含んでもよい医薬中間体である。 Another embodiment of the present invention comprises a pharmaceutically effective amount of sitagliptin complex tannate, a pharmaceutically acceptable polymer such as polyethylene glycol (PEG), such as PEG 3350, PEG 6000 or PEG 8000, and 1 or Pharmaceutical intermediates which may comprise a plurality of pharmaceutically acceptable polyols (eg mannitol or maltitol), high intensity sweeteners (eg sucralose) or flavoring agents (eg mint, cherry or banana flavor).
本発明の別の実施形態は、治療的有効量のタンニン酸シタグリプチン複合体を含む医薬中間体を含む経口剤形(例として錠剤、カプセル、ペレットまたは散剤)である。 Another embodiment of the present invention is an oral dosage form (eg, tablet, capsule, pellet or powder) comprising a pharmaceutical intermediate comprising a therapeutically effective amount of sitagliptin tannate complex.
本発明の別の実施形態は、治療的有効量のタンニン酸シタグリプチン複合体を含む医薬中間体を含む経口剤形であって、この経口剤形はソフトチュー、薬用ガム、チュアブル錠、崩壊錠、シロップ、サッシェ(sachet)、経口フィルム、ゲルまたはリオスフェア(lyosphere)の形態である。 Another embodiment of the present invention is an oral dosage form comprising a pharmaceutical intermediate comprising a therapeutically effective amount of sitagliptin complex tannate, said oral dosage form comprising a soft chew, a medicated gum, a chewable tablet, a disintegrating tablet, In the form of syrup, sachet, oral film, gel or lyosphere.
本発明の別の実施形態は、治療的有効量のタンニン酸シタグリプチン複合体を含む医薬中間体を含む経口剤形(例としてソフトチュー、薬用ガム、経口フィルム、崩壊錠またはシロップ)であって、シタグリプチンが口内でごくわずかな放出を、胃内で即時放出をする経口剤形である。 Another embodiment of the present invention is an oral dosage form (eg soft chew, pharmaceutical gum, oral film, disintegrating tablet or syrup) comprising a pharmaceutical intermediate comprising a therapeutically effective amount of sitagliptin tannate complex, wherein Sitagliptin is an oral dosage form that releases very little in the mouth and immediate release in the stomach.
本発明の別の実施形態は、治療的有効量のタンニン酸シタグリプチン複合体のその必要がある患者への投与を含む、DPP−IVの阻害剤が適応される1または複数の疾患を処置、管理または予防する方法である。 Another embodiment of the present invention is the treatment and management of one or more diseases for which an inhibitor of DPP-IV is indicated, comprising the administration to a patient in need thereof of a therapeutically effective amount of sitagliptin complex tannate. Or a way to prevent.
本発明の別の実施形態は、治療的有効量のタンニン酸シタグリプチン複合体のその必要がある患者への投与を含む、2型糖尿病、肥満および高血圧を処置、管理または予防する方法である。 Another embodiment of the present invention is a method of treating, managing or preventing type 2 diabetes, obesity and hypertension comprising administering to a patient in need thereof a therapeutically effective amount of sitagliptin complex tannate.
本発明の別の実施形態は、DPP−IVの阻害剤が適応される1または複数の疾患の処置および/または予防のための薬剤の製造のためのタンニン酸シタグリプチン複合体の使用である。 Another embodiment of the present invention is the use of sitagliptin tannate complex for the manufacture of a medicament for the treatment and / or prophylaxis of one or more diseases for which an inhibitor of DPP-IV is indicated.
本明細書を通じて用いられるように、以下の用語は、特に指示がない限り、以下の意味を持つと理解されるものである:
「患者」は、ヒトおよび他の動物の両方を包含する。
As used throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" includes both human and other animals.
「哺乳類」は、ヒトおよび他の哺乳動物を包含する。 "Mammal" includes humans and other mammalian animals.
用語「治療的有効量」は、研究者、獣医、医学博士または他の臨床医により求められている組織または系、動物またはヒトの生物学的または医学的な応答(例としてDPP−IVを阻害すること)を誘発する薬学的活性成分の量を意味することが意図される。「予防的有効量」は、研究者、獣医、医学博士または他の臨床医により組織、系、動物またはヒトにおいて予防されることが求められる生物学的または医学的なイベントを予防するまたは発生リスクを低減させる医薬品の量を意味することが意図される。用語「予防すること」または「予防」は、臨床的症状の発症前に化合物を投与することをいうために本明細書中で用いられる。 The term "therapeutically effective amount" refers to a tissue or system sought by a researcher, veterinarian, doctor of medicine or other clinician, biological or medical response of an animal or human (eg DPP-IV as an example) Is intended to mean the amount of pharmaceutically active ingredient that A "prophylactically effective amount" prevents or poses a biological or medical event that is desired to be prevented in a tissue, system, animal or human by a researcher, veterinarian, doctor of medicine or other clinicians It is intended to mean the amount of drug that reduces The terms "preventing" or "prevention" are used herein to refer to administering a compound prior to the onset of a clinical condition.
用語「即時放出」は、USPタイプ2装置の中でpH6.5で室温(約25℃)の空腹時小腸模擬液(FaSSIF)中で試験したときに少なくとも85%の薬が120分以内に剤形から放出されることを意味し、このFaSSIFはSIF(商標)粉末(biorelevant.com Ltdより)を用いて次のように作成することができる:
ステップ1.FaSSIFバッファーの調製(5L)
1.1 5Lを調製するため、以下のものを約4.9Lの精製水中に溶解する:
2.10g NaOH(ペレット)、19.77g リン酸水素ナトリウム一水和物(あるいは17.19g 無水リン酸二水素ナトリウム)、および30.93g NaCl。
The term "immediate release" means that at least 85% of the drug within 120 minutes when tested in fasting small intestine simulated fluid (FaSSIF) at pH 6.5 and room temperature (about 25 ° C) in a USP Type 2 device This FaSSIF can be made as follows using SIFTM powder (from biorelevant.com Ltd), meaning that it is released from the form:
Step 1. Preparation of FaSSIF buffer (5 L)
1. To prepare 5 L, dissolve the following in about 4.9 L of purified water:
2.10 g NaOH (pellet), 19.77 g sodium hydrogen phosphate monohydrate (or alternatively 17.19 g anhydrous sodium dihydrogen phosphate), and 30.93 g NaCl.
1.2 1N NaOHまたは1N HCLのいずれかを用いてバッファーのpHを正確に6.5に調整し、容量を合わせる。 1.2 Adjust the pH of the buffer to exactly 6.5 with either 1 N NaOH or 1 N HCL and combine volumes.
ステップ2.SIF(商標)粉末を用いたFaSSIFの調製(1L);
2.1 1Lメスフラスコの中に、2.24gのSIF(商標)粉末(5℃で保存し、使用前に室温で平衡化したもの)を約500mlのFaSSiFリン酸バッファー中に溶解する。
Step 2. Preparation of FaSSIF using SIF (TM) powder (1 L);
2.1 In a 1 L volumetric flask, dissolve 2.24 g of SIFTM powder (stored at 5 ° C. and equilibrated at room temperature before use) in about 500 ml of FaSSiF phosphate buffer.
2.2 SIF(商標)粉末が分散するまで撹拌する。明澄な溶液が得られたら、FaSSIFリン酸バッファーで容量を合わせる(1L)。 2.2 Stir until the SIFTM powder is dispersed. Once a clear solution is obtained, combine the volumes with FaSSIF phosphate buffer (1 L).
用語「ごくわずかな放出」は、タンニン酸シタグリプチン複合体から解離するシタグリプチンの量がタンニン酸シタグリプチン複合体が対象内でその矯味活性を喪失するほどに十分ではないことを意味し;例として最大10%までのシタグリプチンがタンニン酸シタグリプチン複合体から解離し、最大5%までのシタグリプチンがタンニン酸シタグリプチン複合体から解離し、または最大3%までのシタグリプチンがタンニン酸シタグリプチン複合体から解離する。 The term "very slight release" means that the amount of sitagliptin that dissociates from the tanaginate sitagliptin complex is not sufficient for the tannin sitagliptin complex to lose its taste-masking activity in the subject; for example up to 10 Up to 5% of sitagliptin dissociates from tantate sitagliptin complex, up to 5% sitagliptin dissociates from tannate sitagliptin complex, or up to 3% sitagliptin dissociates from tannate sitagliptin complex.
用語「医薬組成物」は、1より多い(例として2の)薬学的活性剤、例えばタンニン酸シタグリプチン複合体および付加的な活性成分などを含むバルク組成物および個別の投薬単位の両方を包含することが意図される。本発明のタンニン酸シタグリプチン複合体と組み合わせて投与され得るものであって、別々にまたは同じ医薬組成物の中で投与され得る他の薬学的活性成分の例としては、限定されるものではないが、以下が挙げられる:
(a)他のDPP−IV阻害剤;
(b)(i)PPARγアゴニスト、例えばグリタゾン(例としてトログリタゾン、ピオグリタゾン、エングリタゾン、MCC−555、ロシグリタゾンなど)など、ならびにPPARα/γデュアルアゴニスト、例えばKRP−297など、およびPPARαアゴニスト、例えばフェノフィブリン酸誘導体(ゲムフィブロジル、クロフィブラート、フェノフィブラートおよびベザフィブラート)などといった他のPPARリガンド、(ii)ビグアナイド、例えばメトホルミンHClおよびフェンホルミンなど、ならびに(iii)タンパク質チロシンホスファターゼ−1B(PTP−1B)阻害剤を包含するインスリン増感剤;
(c)インスリンまたはインスリン模倣物;
(d)スルホニルウレアおよび他のインスリン分泌促進物質、例えばトルブタミドおよびグリピジド、メグリチニドおよび関連物質など;
(e)α−グルコシダーゼ阻害剤(例えばアカルボースなど);
(f)グルカゴン受容体アンタゴニスト、例えばWO98/04528、WO99/01423、WO00/39088およびWO00/69810中に開示されているものなど;
(g)GLP−1、GLP−1模倣物およびGLP−1受容体アゴニスト、例えばWO00/42026およびWO00/59887中に開示されているものなど;
(h)GIPおよびGIP模倣物、例えばWO00/58360中に開示されているものなど、ならびにGIP受容体アゴニスト;
(i)PACAP、PACAP模倣物およびPACAP受容体3アゴニスト、例えばWO01/23420中に開示されているものなど;
(j)コレステロール低下剤、例えば(i)HMG−CoAレダクターゼ阻害剤(ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、アトルバスタチン、リバスタチン、イタバスタチン、ロスバスタチンおよび他のスタチン)、(ii)捕捉剤(コレスチラミン、コレスチポールおよび架橋デキストランのジアルキルアミノアルキル誘導体)、(iii)ニコチニルアルコール、ニコチン酸またはその塩、(iv)PPARγアゴニスト、例えばフェノフィブリン酸誘導体(ゲムフィブロジル、クロフィブラート、フェノフィブラートおよびベザフィブラート)など、(v)PPARα/γデュアルアゴニスト、例えばKRP−297など、(vi)コレステロール吸収の阻害剤、例えばベータ−シトステロールおよびエゼチミブなど、(vii)アシルCoA:コレステロールアシルトランスフェラーゼ阻害剤、例えばアバシミベなど、ならびに(viii)抗酸化剤、例えばプロブコールなど;
(k)PPARδアゴニスト、例えばWO97/28149中に開示されているものなど;
(l)抗肥満化合物、例えばフェンフルラミン、デクスフェンフルラミン、フェンテルミン、シブトラミン、オルリスタット、神経ペプチドY5阻害剤およびβ3アドレナリン受容体アゴニストなど;
(m)回腸胆汁酸トランスポーター阻害剤;ならびに
(n)炎症状態における使用が意図される剤、例えばアスピリン、非ステロイド性抗炎症薬、グルココルチコイド、アザルフィジンおよびシクロ−オキシゲナーゼ2選択的阻害剤など。
The term "pharmaceutical composition" encompasses both bulk compositions and individual dosage units which comprise more than one (for example 2) pharmaceutically active agents such as sitagliptin tannate complex and additional active ingredients etc. Is intended. Examples of other pharmaceutically active ingredients which may be administered in combination with the tantagate sitagliptin complex of the present invention and which may be administered separately or in the same pharmaceutical composition include, but are not limited to: , Include:
(A) Other DPP-IV inhibitors;
(B) (i) PPARγ agonists such as glitazones (eg troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone etc) etc., as well as PPARα / γ dual agonists such as KRP-297 etc. and PPARα agonists such as pheno Other PPAR ligands such as fibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin HCl and phenformin, and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors Including insulin sensitizers;
(C) insulin or insulin mimics;
(D) sulfonylureas and other insulin secretagogues, such as tolbutamide and glipizide, meglitinide and related substances;
(E) α-glucosidase inhibitor (eg acarbose etc.);
(F) glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810;
(G) GLP-1, GLP-1 mimetics and GLP-1 receptor agonists such as those disclosed in WO 00/42026 and WO 00/59887;
(H) GIP and GIP mimetics, such as, for example, those disclosed in WO 00/58360, and GIP receptor agonists;
(I) PACAP, PACAP mimetics and PACAP receptor 3 agonists such as those disclosed in WO 01/23420;
(J) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin and other statins), (ii) scavengers (cholestyramine, (C) dialkylaminoalkyl derivatives of cholestipol and cross-linked dextrans), (iii) nicotinyl alcohol, nicotinic acid or salts thereof, (iv) PPARγ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), etc. (v ) PPARα / γ dual agonists such as KRP-297, (vi) inhibitors of cholesterol absorption such as beta-sitosterol and ezeti Such blanking, (vii) acyl CoA: cholesterol acyltransferase inhibitors, such as avasimibe, and (viii) anti-oxidants, such as probucol;
(K) PPARδ agonists such as those disclosed in WO 97/28149;
(L) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors and β3 adrenergic receptor agonists;
(M) ileal bile acid transporter inhibitors; and (n) agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azalfidine and cyclo-oxygenase 2 selective inhibitors.
上の組み合わせは、本発明のタンニン酸シタグリプチン複合体と1の他の薬学的活性成分との組み合わせのみならず、2またはそれより多い異なる薬学的活性成分との組み合わせを包含する。限定されない例としては、タンニン酸シタグリプチン複合体とビグアナイド、スルホニルウレア、HMG−CoAレダクターゼ阻害剤、PPARアゴニスト、PTP−1B阻害剤、他のDPP−IV阻害剤および抗肥満化合物から選択される2またはそれより多い薬学的活性成分との組み合わせが挙げられる。 The above combinations include not only the combination of the tantagate sitagliptin complex of the present invention with one other pharmaceutically active ingredient, but also the combination of two or more different pharmaceutically active ingredients. Non-limiting examples include tannate sitagliptin complex and biguanide, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DPP-IV inhibitors and two or more selected from anti-obesity compounds Combinations with more pharmaceutically active ingredients are included.
バルク組成物および各々の個別の投薬単位は、固定量の前記「1より多い薬学的活性剤」を含有することができる。バルク組成物は、まだ個別の投薬単位へと形成されていない物質である。例証的な投薬単位は、経口投薬単位、例えば錠剤、丸剤などである。同様に、本明細書中に記載されている、本発明の医薬組成物を投与することにより患者を処置する方法もまた、前記バルク組成物および個別の投薬単位の投与を包含することが意図される。 The bulk composition and each individual dosage unit can contain a fixed amount of the "more than one pharmaceutically active agent". Bulk compositions are substances that have not yet been formed into discrete dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Likewise, the methods of treating a patient by administering a pharmaceutical composition of the invention as described herein are also intended to encompass the administration of said bulk composition and individual dosage units. Ru.
本発明の経口投薬量は、適応される効能のために用いられる場合、約0.01mg/kg体重/日(mg/kg/日)から約100mg/kg/日、好ましくは0.01から10mg/kg/日、および最も好ましくは0.1から5.0mg/kg/日の範囲にある。経口投与の場合、組成物は、好ましくは、処置される患者への投薬量の対症的調整のため、0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、200および500ミリグラムのシタグリプチンを含有する経口剤形の形態で提供される。薬剤は、典型的に約0.01mgから約500mgのシタグリプチン、好ましくは約1mgから約200mgの活性成分を含有する。 The oral dosage of the present invention is about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day, preferably 0.01 to 10 mg, when used for the indicated efficacy. / Kg / day, and most preferably in the range of 0.1 to 5.0 mg / kg / day. For oral administration, the composition is preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5 for symptomatic adjustment of the dose to the patient being treated. , 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200 and 500 milligrams of sitagliptin are provided in the form of an oral dosage form. The medicament typically contains about 0.01 mg to about 500 mg of sitagliptin, preferably about 1 mg to about 200 mg of the active ingredient.
本発明の方法において、タンニン酸シタグリプチン複合体は、医薬品有効成分を形成することができ、典型的に、意図される投与形態、すなわち経口錠剤、カプセル、エリキシル剤、シロップなどに対して好適に選択される、慣用的な医薬の実務と一致した好適な医薬希釈剤、添加剤または担体(本明細書中であわせて「担体」物質と呼ばれる)と混合されて投与される。 In the method of the present invention, sitagliptin tannate complex can form an active pharmaceutical ingredient, and is typically selected suitably for the intended dosage form, ie oral tablets, capsules, elixirs, syrups etc. A suitable pharmaceutical diluent, additive or carrier (collectively referred to herein as a "carrier" substance) is administered in combination with conventional pharmaceutical practice.
例えば、錠剤またはカプセルの形態での経口投与の場合、医薬品有効成分は、経口の、非毒性の、薬学的に許容される不活性担体、例えば乳糖、デンプン、ショ糖、グルコース、メチルセルロース、ステアリン酸マグネシウム、リン酸二カルシウム、硫酸カルシウム、マンニトール、ソルビトールなどと組み合わせることができ;液体形態での経口投与の場合、医薬品有効成分は、経口の、非毒性の、薬学的に許容される不活性担体、例えばエタノール、グリセロール、水などと組み合わせることができる。そのうえ、所望または必要であるとき、付加的な薬学的に許容されるアジュバントを加えてもよい。付加的な医薬アジュバントとしては、バインダー、滑沢剤、甘味料、香味剤、崩壊剤および着色料が挙げられ、これらは当該技術分野で公知である(例としてRemington’s Pharmaceutical Sciences(1995)を参照されたい)。好適なバインダーとしては、デンプン、ゼラチン、天然の糖、例えばグルコースまたはベータ−ラクトースなど、コーン甘味料、天然および合成のガム、例えばアカシア、トラガカントまたはアルギン酸ナトリウムなど、カルボキシメチルセルロース、ポリエチレングリコール、ワックスなどが挙げられる。これらの剤形において用いられる滑沢剤としては、オレイン酸ナトリウム、ステアリン酸ナトリウム、ステアリン酸マグネシウム、安息香酸ナトリウム、酢酸ナトリウム、塩化ナトリウムなどが挙げられる。崩壊剤としては、限定されるものではないが、デンプン、メチルセルロース、寒天、ベントナイト、キサンタンガムなどが挙げられる。 For example, for oral administration in the form of a tablet or capsule, the pharmaceutical active ingredient may be an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, stearic acid It can be combined with magnesium, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc .; for oral administration in liquid form, the active pharmaceutical ingredient is an oral, non-toxic, pharmaceutically acceptable inert carrier For example, it can be combined with ethanol, glycerol, water and the like. Moreover, additional pharmaceutically acceptable adjuvants may be added when desired or necessary. Additional pharmaceutical adjuvants include binders, lubricants, sweeteners, flavoring agents, disintegrants and coloring agents, which are known in the art (for example, Remington's Pharmaceutical Sciences (1995)). See for reference). Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes etc. It can be mentioned. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
タンニン酸シタグリプチン複合体を調製するための一般的方法
本発明のタンニン酸シタグリプチン複合体は、次のプロセスにより作成することができる:
(1)薬学的に許容される溶媒(例としてメタノールまたはエタノール)中の遊離塩基形態のシタグリプチンについての塩の溶液を、薬学的に許容される溶媒(例としてメタノールまたはエタノール)中のタンニン酸分散物と撹拌しながら合わせることで、第一の混合物を形成し;
(2)第一の混合物から、例えば、蒸発、デカンテーションまたは真空乾燥により大半の液体を除去し;
(3)ステップ(2)において得られた残渣を極性の薬学的に許容される液体(例として水)で洗浄し;
(4)ステップ(3)において得られた洗浄された残渣から、例えば、蒸発、デカンテーションまたは真空乾燥により全ての液体を除去し;
(5)ステップ(4)において得られた残渣を、例えば、(例として50℃の)真空オーブン中で約3から10時間乾燥させることで、タンニン酸シタグリプチン複合体を提供し;
(6)タンニン酸シタグリプチン複合体を(例としてミリングによって)粉砕して、易流動性の粉末にする。
General Methods for Preparing Tannate Sitagliptin Complex The tannate sitagliptin complex of the present invention can be made by the following process:
(1) Dispersion of a solution of a salt for sitagliptin in free base form in a pharmaceutically acceptable solvent (eg methanol or ethanol) in a tannic acid dispersion in a pharmaceutically acceptable solvent (eg methanol or ethanol) Forming a first mixture by combining with the substance while stirring;
(2) Remove most of the liquid from the first mixture, for example, by evaporation, decantation or vacuum drying;
(3) washing the residue obtained in step (2) with a polar pharmaceutically acceptable liquid (eg water);
(4) Remove all liquid from the washed residue obtained in step (3), for example by evaporation, decantation or vacuum drying;
(5) drying the residue obtained in step (4), for example, in a vacuum oven (for example at 50 ° C.) for about 3 to 10 hours to provide sitagliptin tannate complex;
(6) The tannin acid sitagliptin complex is ground (eg, by milling) to a free flowing powder.
タンニン酸シトグリプチン(SITGLIPTIN)複合体
実施例1
シタグリプチンの活性溶液は、0.5gのシタグリプチン遊離塩基を20mlのメタノール中に溶解することにより調製した。1gのタンニン酸を同量のメタノール中に溶解することで、タンニン酸分散物を形成させた。シタグリプチン溶液を次いで撹拌しながらタンニン酸分散物に徐々に加えた。全ての溶媒をドラフト内の環境条件下で蒸発させるまで、混合物を撹拌した。形成された固形の物質を粉砕して粉末にした。100mlの水を粉末に加え、混合物を30分間撹拌した後、15000rpmで遠心分離することで液体を除去した。洗浄したタンニン酸シタグリプチン複合体を次いで50℃の恒温オーブン内で乾燥させた。
Sitogliptin tannate (SITGLIPTIN) complex Example 1
An active solution of sitagliptin was prepared by dissolving 0.5 g of sitagliptin free base in 20 ml of methanol. A tannic acid dispersion was formed by dissolving 1 g of tannic acid in the same amount of methanol. The sitagliptin solution was then slowly added to the tannic acid dispersion with stirring. The mixture was stirred until all solvent was evaporated under ambient conditions in the fume hood. The solid material formed was ground to a powder. 100 ml of water was added to the powder and the mixture was stirred for 30 minutes before removing liquid by centrifuging at 15000 rpm. The washed sitagliptin tannate complex was then dried in a 50 ° C. constant temperature oven.
実施例2
1.5gのシタグリプチン遊離塩基の溶液、および3gのタンニン酸の分散物を、20mlのエタノール中に別々に調製した。少量のシタグリプション(sitagliption)溶液をタンニン酸分散物に撹拌しながら加えた。全てのシタグリプチン溶液を加えた後、全ての溶媒を蒸発させるまで、混合物をドラフト内の環境条件下で撹拌した。固形の物質をさらに、50℃の真空オーブン内で3時間乾燥させた。これを次いで粉砕して粉末にした。
Example 2
A solution of 1.5 g of sitagliptin free base and a dispersion of 3 g of tannic acid were prepared separately in 20 ml of ethanol. A small amount of sitagliption solution was added to the tannic acid dispersion with stirring. After all sitagliptin solution was added, the mixture was stirred under ambient conditions in a fume hood until all solvent was evaporated. The solid material was further dried in a 50 ° C. vacuum oven for 3 hours. It was then ground to a powder.
2段階の溶解プロファイル
次の2段階の溶解プロトコールを用いることによる、模擬唾液(SSF)および模擬胃液(SGF)を用いた実施例1および2のタンニン酸シタグリプチン複合体の溶解プロファイル:
段階1:8.0gのNaCl、0.19gの一塩基性リン酸カリウムおよび2.38gの二塩基性リン酸ナトリウムを1Lの水中に溶解し、リン酸でpH6.8に調整することによりSSFを調製し、10mLのSSF中に実施例1または2のタンニン酸シタグリプチン複合体の試料を入れた。37℃まで1分間加温し、一定分量を取り出した。
Two-Step Dissolution Profile Dissolution profile of the tannin sitagliptin complex of Examples 1 and 2 using simulated saliva (SSF) and simulated gastric fluid (SGF) by using the following two-step lysis protocol:
Step 1: SSF by dissolving 8.0 g of NaCl, 0.19 g of monobasic potassium phosphate and 2.38 g of dibasic sodium phosphate in 1 L of water and adjusting to pH 6.8 with phosphoric acid Was prepared, and a sample of sitagliptin tannate complex of Example 1 or 2 was placed in 10 mL of SSF. Warm to 37 ° C. for 1 minute and take out aliquots.
段階2:2.0gのNaClを1Lの水中に溶解し、1.4mLの濃塩酸を加えることによりSGFを調製し、500mLのSGFに上の残りの溶液を移した。SGFを37℃において装置2(パドル)で撹拌し、6つの時点で一定分量を採取した。 Step 2: SGF was prepared by dissolving 2.0 g of NaCl in 1 L of water, adding 1.4 mL of concentrated hydrochloric acid, and transferring the remaining solution to 500 mL of SGF. The SGF was stirred at 37 ° C. with apparatus 2 (paddle) and aliquots were taken at six time points.
この一定分量を次いでHPLCにより分析することで、遊離シタグリプチン量を決定した。 This aliquot was then analyzed by HPLC to determine the amount of free sitagliptin.
図1は実施例1の溶解プロファイルを描写し、図2は実施例2の溶解プロファイルを描写している。両プロファイルは、SSF中でシタグリプチンはごく少量しか放出されないか、または放出されないことを指し示している。このことは、シタグリプチン−タンニン酸複合体は中性pHで可溶性ではない、またはほぼ可溶性ではないことを指し示しており、したがって、対象はシタグリプチンの不快な味を感じるとは予想されない。しかしながら、両プロファイル中で、シタグリプチンはSGFの低いpHにおいて複合体から迅速に放出されており、それ故に、対象による吸収に利用可能であると予想される。 FIG. 1 depicts the dissolution profile of Example 1, and FIG. 2 depicts the dissolution profile of Example 2. Both profiles indicate that only small amounts of sitagliptin are released in SSF. This indicates that sitagliptin-tannic acid complex is not soluble or nearly soluble at neutral pH, and therefore, the subject is not expected to feel the unpleasant taste of sitagliptin. However, in both profiles, sitagliptin is rapidly released from the complex at low pH of SGF and is therefore expected to be available for absorption by the subject.
製剤例
ソフトチュー
実施例1および2において得られたタンニン酸シタグリプチン複合体を、次の組成のタンニン酸シタグリプチン複合体を組み入れることによりソフトチューとして製剤化した:
ソフトチュー製剤は、次のように調製した:
(1)A部の成分を均一になるまで混合し;
(2)B部の成分を混合し;
(3)C部の成分をタービュラーミキサー(turbular mixer)内で約10分間混合し;
(4)ステップ(2)からの混合された成分を溶かしてステップ(1)の混合された成分に加えてよく混合し;
(5)ステップ(3)からの混合された成分をステップ(4)からの混合された成分に加えて均一になるまで混合し;
(6)ペパーミントをステップ(5)中で得られた混合物に加えてよく混合することで、生地様の混合物を得て;
(7)生地様の混合物をソフトチューの型に入れ、固めて、実施例1または実施例2のタンニン酸シタグリプチン複合体を含有するソフトチュー単位を形成させた。
The soft chew formulation was prepared as follows:
(1) Mix the components of part A until uniform;
(2) Mix the ingredients of part B;
(3) Mix the components of part C for about 10 minutes in a turbular mixer;
(4) Melt the mixed components from step (2) and add to the mixed components of step (1) and mix well;
(5) Add the mixed components from step (3) to the mixed components from step (4) and mix until uniform;
(6) Add peppermint to the mixture obtained in step (5) and mix well to obtain a dough-like mixture;
(7) The dough-like mixture was placed in a mold of soft chew and solidified to form a soft chew unit containing sitagliptin tannate complex of Example 1 or Example 2.
本発明はそのある特定の実施形態を参照して記載されているが、本明細書中に記載されている教示から多数の代替的実施形態が当業者に明らかである。特許請求の範囲は、例中に記述されている好ましい実施形態に限定されるべきではなく、全体としての記載に一致した最も広い解釈が与えられるべきである。本明細書中で引用されている全ての特許、特許出願および刊行物は、参照によりその全体が組み入れられる。 Although the present invention has been described with reference to certain specific embodiments thereof, numerous alternative embodiments will be apparent to those skilled in the art from the teachings set forth herein. The claims should not be limited to the preferred embodiments described in the examples, but should be given the broadest interpretation consistent with the description as a whole. All patents, patent applications and publications cited herein are incorporated in their entirety by reference.
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US8003672B2 (en) * | 2008-04-21 | 2011-08-23 | Merck Sharp & Dohme Corp. | CB-1 receptor modulator formulations |
EP2218721A1 (en) | 2009-02-11 | 2010-08-18 | LEK Pharmaceuticals d.d. | Novel salts of sitagliptin |
US9211263B2 (en) * | 2012-01-06 | 2015-12-15 | Elcelyx Therapeutics, Inc. | Compositions and methods of treating metabolic disorders |
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2015
- 2015-04-13 JP JP2016562508A patent/JP6523328B2/en active Active
- 2015-04-13 US US15/302,211 patent/US9833463B2/en active Active
- 2015-04-13 AU AU2015247921A patent/AU2015247921B2/en active Active
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- 2015-04-13 BR BR112016023839A patent/BR112016023839A8/en not_active Application Discontinuation
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CN106456998A (en) | 2017-02-22 |
ES2932383T3 (en) | 2023-01-18 |
US20170042922A1 (en) | 2017-02-16 |
EP3131631A4 (en) | 2017-11-29 |
JP2017511350A (en) | 2017-04-20 |
AU2015247921B2 (en) | 2019-07-11 |
RU2016144695A3 (en) | 2018-10-11 |
CA2945681A1 (en) | 2015-10-22 |
MX2016013588A (en) | 2017-01-26 |
RU2696588C2 (en) | 2019-08-05 |
CN106456998B (en) | 2020-07-28 |
BR112016023839A2 (en) | 2017-08-15 |
EP3131631B1 (en) | 2022-11-16 |
EP3131631A1 (en) | 2017-02-22 |
BR112016023839A8 (en) | 2023-04-11 |
KR20160145008A (en) | 2016-12-19 |
KR102351813B1 (en) | 2022-01-18 |
AU2015247921A1 (en) | 2016-10-13 |
US9833463B2 (en) | 2017-12-05 |
RU2016144695A (en) | 2018-05-21 |
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